There are many applications which require mixing liquids in controlled proportions. One such application is liquid chromatography wherein a liquid sample is passed by a flowing stream of liquid solvent (the mobile phase) through a column packed with particulate matter (the stationary phase). While passing through the column, the various components in the sample separate from one another by adsorbing and desorbing from the stationary phase at different rates such that these individual components elute from the column at different times. The separated components then flow through a detector which responds to each component both qualitatively and quantitatively, thereby providing information to the user about the constituents of the sample.
To achieve more effective separations, high performance liquid chromatography (HPLC) systems often use mixtures of solvents as the mobile phase. When this mixture is held constant, the system operates in an isocratic mode, whereas gradient chromatography is achieved when the components of the mixture are changed over time. The present invention has particular utility to both modes of operation.
Such mixtures of chromatographic solvents can be accomplished by having redundant high pressure pumps with each pump delivering its precise portion of liquid required to a mixing chamber downstream of the pump (i.e., high pressure side). However, these pumps are expensive, and the overall cost and complexity of the system is undesirably increased.
Alternatives have been proposed in the past to perform the desired metering at the low pressure side of the pump. Most often such systems include a plurality of reservoirs containing the liquids to be mixed, with each reservoir being suitably connected to the inlet of the pump. A valve arrangement between the reservoirs and the pump inlet meters each liquid in predetermined proportions. To meter the solvent volumes, the individual valves are sequentially actuated during the pump draw stroke. However, the draw stroke of the pump is non-uniformly related to the amount of liquid taken into the chamber. This is due to a combination of two effects--firstly, compressibility of both the liquid remaining in the chamber from the preceding delivery stroke and of certain internal pump components such as seals, which must first decompress before fresh liquid is taken in, and secondly, the non-uniform velocity of the piston during the draw stroke. Moreover, the long lengths of tubing from the solvent reservoirs to the switching valve arrangement create a hydraulic inertia that has detrimental effects during valve switching. Therefore, significant errors in the compositional mixture can result from these problems. Some of these errors vary over time and produce a compositional error that is detected as a "ripple" which interferes with the ability to detect and quantitate chromatographic peaks.
There have been many attempts to overcome the problems associated with these low pressure metering techniques, and much effort has been expended in attempting to produce accurate isocratic and gradient mixtures for HPLC mobile phases. Generally these attempts can be classified into three types--open loop averaging, open loop with compensation, and feedback. An example of the averaging technique is shown in U.S. Pat. No. 3,869,067 whose teaching is based on the premise that the desired composition is directly proportional to the actuation time of the individual valves in the system as a percentage of the total cycle time for actuation of all the valves. Since the rate at which fluid is drawn into the pump varies over time, simple time proportioning of valve actuation produces inaccurate, time varying compositions. To minimize these inaccuracies, the valves are actuated as frequently as possible so that the flow has not significantly changed between subsequent valve cycles. However, in this approach, the valve actuation times establish a limit on the frequency of actuation, particularly for lower percent composition values. Moreover, this technique still does not effectively address the non-uniform pump fluid draw stroke problem as large errors can occur if the valve cycle is in synchronism with the pump cycle.
U.S. Pat. No. 4,045,343 discloses a variation of the open loop averaging technique. The liquid composition is determined once again by the relative time each valve is opened in the cycle of actuation of all valves, but in this instance initiation of the switching valve cycle is delayed by a predetermined amount of pump stroke to correct for the non-uniformity due to compressibility during the pump draw stroke. However, the non-uniformity associated with pump draw stroke changes with different solvents and with differnt system back pressures so that the delay-factor compensation can only approximately compensate for the effect of such non-uniformity resulting in poor accuracy.
An example of the feedback type is shown in U.S. Pat. No. 4,128,476. Here a feedback error signal, which is derived from a measurement of system back pressure, is employed to alter the relative times each switching valve is opened during the pump draw stroke cycle. However, the measured parameter is indirectly related to composition, and moreover, this measurement is effected by external pressure influencing factors such as sample injections. Furthermore this feedback arrangement adds an overall degree of complexity and cost to the system that in certain applications is commercially undesirable.
Other attempts to minimize the interaction between valve cycles and pump cycles in a liquid chromatography multiple solvent delivering system are found in U.S. Pat. No. 4,427,298 and in an article by D. L. Saunders entitled, "A Versatile Gradient Elution Device for HPLC" (Journal of Chromatographic Science, Vol. 15, March/April 1977). Both of these references recognize that there are certain relationships between the pump cycle rate and the switching valve period that are to be avoided, namely values of valve cycle time which closely correspond to whole number multiples of the pump cycle time. However, neither reference is concerned with inaccuracies involved in such systems that are attributable to fluid inertia effects, particularly at high flow rates and also at short valve duration times.
It is apparent from the foregoing that the need exists for an accurate, reproducible technique for metering liquids in controlled proportions with minimum cost and complexity.